Decreasing the production of Abeta may be beneficial in the treatment of Alzheimer's Disease (AD). Basic research carried out through Projects 1 and 2 previously identified that allosteric modulators of gamma- secretase selectively lower Abeta42, without affecting Notch processing, and screened several Nonsteriodal anti-inflammatory drugs (NSAIDS) as candidates. We designed and conducted'a clinical trial to determine :he safety, tolerability and pharmacokinetics of R-flurbiprofen in healthy older adults. The data was used by Myriad Pharmaceuticals, Inc.,to plan and implement phase 2 and an ongoing program of phase 3 clinical trials of R-flurbiprofen in AD. In this renewal of Project 3, we aim to optimize biomarker measurements of Abeta in CSF to characterize Abeta lowering effects of R-flurbiprofen. We also aim to test ibuprofen, an NSAID with gamma-secretase modulating activity and anti-inflammatory actions, by carrying out a controlled clinical trial in patients with amnestic Mild Cognitive Impairment (aMCI), the earliest clinically diagnosable stage of AD. This targets early intervention, before patients have developed extensive amyloid deposition and damage to neurons and synapses. We hypothesize that lowering Abeta42 very early in AD may have beneficial effects on imaging and biochemical biomarkers. We have 2 aims: (1) To evaluate CSF levels of Abeta42 after acute treatment with R-flurbiprofen at a high dose of 1600mg in healthy adults, using a lumbar CSF catheter to obtain CSF samples during 24 hours, and the technique of stable isotopic labeling to calculate Abeta synthesis rates. This will characterize the timing and duration of Abeta lowering actions. (2) To evaluate biomarker changes in CSF and brain atrophy measures on MRI,in 100 patients with aMCI who will be randomized to treatment with ibuprofen 800 mg three times per day (+ omeprazole 20 mg/day for gastroprotection), or to placebo, for 12 months. CSF and MRI will be obtained at baseline and 12 months and a brief neuropsychological test battery (NTB) and lADL-questionnaire will be given at baseline, 6 and 12 months. Primary outcome measures will be change in hippocampal and total brain volume (MRI); concentrations of total tau, phosphotau 181,Abeta42 and Abeta38, and F2-isoprostanes (CSF). Secondary outcome measures will be change in NTB and ADCS ADL-MCI scores. Significance: No treatment has been shown to have disease-modifying effects in AD. CSF biomarkers and MRI measures allow us to monitor whether treatment that targets modulation of gamma-secretase will (1) selectively lower Abeta42 in humans following acute treatment; (2) have beneficial effects on biomarkers related to Abeta and to damage from the resulting cascade of pathology in aMCI, the earliest clinical stage at which AD can be diagnosed. These results will support further efforts to develop gamma-secretase modulators for early clinical use.